EP0055899B1 - Antiallergic imidodisulfamides, process for their production and pharmaceutical compositions containing them - Google Patents
Antiallergic imidodisulfamides, process for their production and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- EP0055899B1 EP0055899B1 EP81305796A EP81305796A EP0055899B1 EP 0055899 B1 EP0055899 B1 EP 0055899B1 EP 81305796 A EP81305796 A EP 81305796A EP 81305796 A EP81305796 A EP 81305796A EP 0055899 B1 EP0055899 B1 EP 0055899B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- chloro
- compound
- methyl
- alkali metal
- metal salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title claims abstract description 6
- 230000003266 anti-allergic effect Effects 0.000 title 1
- PVMUVDSEICYOMA-UHFFFAOYSA-N n-chlorosulfonylsulfamoyl chloride Chemical class ClS(=O)(=O)NS(Cl)(=O)=O PVMUVDSEICYOMA-UHFFFAOYSA-N 0.000 claims abstract description 8
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000007530 organic bases Chemical class 0.000 claims abstract description 4
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 3
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 44
- -1 bromo, chloro, nitro, methyl Chemical group 0.000 claims description 19
- 229910052783 alkali metal Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 208000024891 symptom Diseases 0.000 claims description 4
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000043 antiallergic agent Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 208000026935 allergic disease Diseases 0.000 abstract description 5
- 238000011282 treatment Methods 0.000 abstract description 5
- 206010027654 Allergic conditions Diseases 0.000 abstract 1
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 14
- 210000001519 tissue Anatomy 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000000556 agonist Substances 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 0 O=NC(C1)C=CC(CC2)=C1C*2N=O Chemical compound O=NC(C1)C=CC(CC2)=C1C*2N=O 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 206010002198 Anaphylactic reaction Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000036783 anaphylactic response Effects 0.000 description 3
- 208000003455 anaphylaxis Diseases 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 230000008602 contraction Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- YVOKSMUYOSRIFD-UHFFFAOYSA-N 1-(7-sulfanyl-3,4-dihydro-1h-isoquinolin-2-yl)ethanone Chemical compound C1=C(S)C=C2CN(C(=O)C)CCC2=C1 YVOKSMUYOSRIFD-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000006199 nebulizer Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- OABMDQQWNSVORX-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-(1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethanone Chemical compound C1=CC(Cl)=CC=C1C(=O)CS(=O)(=O)C1=CC=C(CCNC2)C2=C1 OABMDQQWNSVORX-UHFFFAOYSA-N 0.000 description 1
- YCLKWPNOVWNQDY-UHFFFAOYSA-N 1-phenyl-2-(1,2,3,4-tetrahydroisoquinolin-7-ylsulfonyl)ethanone Chemical compound C=1C=C2CCNCC2=CC=1S(=O)(=O)CC(=O)C1=CC=CC=C1 YCLKWPNOVWNQDY-UHFFFAOYSA-N 0.000 description 1
- CYXIKYKBLDZZNW-UHFFFAOYSA-N 2-Chloro-1,1,1-trifluoroethane Chemical compound FC(F)(F)CCl CYXIKYKBLDZZNW-UHFFFAOYSA-N 0.000 description 1
- AKWMTTOSEHZBQK-UHFFFAOYSA-N 2-[(2-acetyl-3,4-dihydro-1h-isoquinolin-7-yl)sulfanyl]-1-phenylethanone Chemical compound C1=C2CN(C(=O)C)CCC2=CC=C1SCC(=O)C1=CC=CC=C1 AKWMTTOSEHZBQK-UHFFFAOYSA-N 0.000 description 1
- MULMLDROTQLKML-UHFFFAOYSA-N 2-acetyl-3,4-dihydro-1h-isoquinoline-7-sulfonyl chloride Chemical compound C1=C(S(Cl)(=O)=O)C=C2CN(C(=O)C)CCC2=C1 MULMLDROTQLKML-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- WJGAPUXHSQQWQF-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O WJGAPUXHSQQWQF-UHFFFAOYSA-N 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical class BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229960002816 potassium chloride Drugs 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/08—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with a hetero atom directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B21/00—Nitrogen; Compounds thereof
- C01B21/082—Compounds containing nitrogen and non-metals and optionally metals
- C01B21/087—Compounds containing nitrogen and non-metals and optionally metals containing one or more hydrogen atoms
- C01B21/093—Compounds containing nitrogen and non-metals and optionally metals containing one or more hydrogen atoms containing also one or more sulfur atoms
- C01B21/0935—Imidodisulfonic acid; Nitrilotrisulfonic acid; Salts thereof
Definitions
- This invention relates to novel imidodisulfamides which are useful as end-organ antagonists or slow reacting substance of anaphylaxis, pharmaceutical compositions and methods of inibiting the symptoms of an allergic response.
- the substance, SRS-A has been suggested to be an important mediator of anaphylaxis in human asthma. By antagonizing the effects of this or other pharmacologically active mediators at the end-organ, bronchial smooth muscle, the compounds of this invention are valuable in the treatment of allergic diseases such as asthma.
- the imidodisulfamide compounds of this invention are represented by the following general structural formula (I): wherein R i is hydrogen, bromo, chloro, nitro, methyl, trifluoromethyl or methoxy and R 2 is hydrogen, chloro or methyl with the proviso that when R 2 is chloro, R 1 is chloro, methyl or trifluoromethyl; and alkali metal salts of said compounds.
- non-nucleophilic organic bases examples include tertiary alkylamines, such as triethylamine, tertiary alkylaryl amines, such as N,N-dimethylaniline and aromatic amines, such as pyridine.
- the reaction is carrried out in an inert polar organic solvent.
- a particular solvent is not critical provided that the solvent is substantially inert to the reagents and product.
- Illustrative of such a solvent is acetonitrile.
- the reaction is usually carried out at moderate to low temperatures.
- the reagents are usually mixed at temperatures of 0°C. or less and the reaction is allowed to warm gradually to ambient temperature.
- reaction time is dependent on inter alia the particular starting materials, solvent and reaction temperature. Generally, the reaction will be allowed to proceed for at least 12 hours.
- reaction product can be isolated by standard methods, for example, addition of dilute mineral acid e.g. hydrochloric acid, to the reaction mixture affords the compounds of general formula (1) as the "free acid".
- dilute mineral acid e.g. hydrochloric acid
- Alkali metal salts of the compounds of the general formula (I), for example, the sodium or potassium salts are obtainable by treatment of the compounds with the appropriate metal alkoxide, for example methoxide, in an alkanol solvent such as methanol; by treatment of the compounds with an alkali metal hydride, such as sodium hydride or potassium hydride, in a polar non-protic solvent, such as tetrahydrofuran, or dimethoxyethane; or by treatment of the compounds with a cationic exchange resin, such as sulfonic acid resin in the sodium form.
- the appropriate metal alkoxide for example methoxide
- an alkanol solvent such as methanol
- an alkali metal hydride such as sodium hydride or potassium hydride
- a polar non-protic solvent such as tetrahydrofuran, or dimethoxyethane
- a cationic exchange resin such as sulfonic acid resin in the sodium form.
- the starting appropriately substituted tetrahydroisoquinolines of the general formula (A) are conveniently prepared by standard reactions well known in the chemical arts as shown below: 2-Acetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline, which is prepared by acylating and then chlorosulfonating 1,2,3,4-tetrahydroisoquinoline, is reduced to 2-acetyl-7-mercapto-1,2,3,4-tetrahydroisoquinoline employing stannous chloride in acetic acid-hydrochloric acid mixture.
- the 2-acetyl-7-mercapto-1,2,3,4-tetrahydroisoquinoline is then condensed with the appropriately substituted ⁇ -bromo acetophenone to afford 2-acetyl-7-benzoylmethylthio-1,2,3,4-tetrahydroisoquinoline (B) which is then oxidized with m-chloroperbenzoic acid and hydrolyzed to yield the desired 7-benzoylmethylsulfonyl-1,2,3,4-tetrahydroisoquinoline (A).
- Bis(chlorosulfonyl)imide is prepared from chlorosulfonic acid and chlorosulfonylisocyanate.
- the SRS-A antagonist activity of the compounds of this invention is measured by the ability of the active medicament to inhibit SRS-A induced contraction of guinea pig ileum.
- sections of ileum are resected from guinea pigs and placed in 5 ml. tissue baths containing a modified Tyrode's solution. One end of the tissue is fixed to a glass tissue holder, the other is connected to a force-displacement transducer and the tissue is placed under a tension of 500 mg. Isometric tissue contractions are recorded on a six channel polygraph.
- Baths are constantly aerated with 95% O 2 ⁇ 5% CO 2 , After a 20 minute stabilization period a concentration of the appropriate agonist which provides a contraction height of 60-80% of the maximum obtainable to that agonist (as determined from full sequential concentration - response curves in separate experiments) is added to the tissue bath and the response recorded. The procedure is repeated until reproducible responses are obtained. For most agonists, two applications in rapid succession, followed 15 minutes later by a third, is sufficient to establish reproducibility. Experimental tissues are incubated with the selected concentration of the test compounds for 1 minutes. Experimental and control tissues are subjected to 5 bath changes during the incubation interval. Changes in bath fluid during the incubation period are helpful in insuring the reproducibility of tissue responses to the agonist.
- the same concentration of the agonist is reapplied in the presence of the test compound and the response registered and compared with controls.
- Percent inhibition produced by the test compound is calculated by subtracting the mean percentage change in control tissue from the mean percentage change in tissues exposed to the test compound. Additional compounds are then evaluated as long as the tissue remains reproducibly responsive to the agonist. Six tissues obtained from 6 animals are used simultaneously - 3 controls and 3 experimental.
- the compounds of this invention tested at concentrations of from 5 x 10- 5 M to 1 x 10- 6 M produce marked antagonism or partially purified slow reacting substance of anaphylaxis obtained from guinea pig lung.
- the agonist is employed at a concentration of 40,ug/ml.
- N,N'-bis[7-(4-chlorobenzoylmethylsulfonyl)-1,2,3,4-tetrahydroisoquinoyl]disulfonylimide exhibited 60 percent antogonism.
- the specificity of the antagonist activity of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, serotonin, histamine and the prostaglandins F2,, and E 2 .
- compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the general formula (1) or an alkali metal salt thereof sufficient to produce the inhibition of the symptoms of asthma and other allergic diseases.
- examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide.
- the instant compositions may include other ingredients such as, stabilizers, antioxidants, preservatives, lubricants, suspending agents and viscosity modifiers, provided that the additional ingredients do not have detrimental effect on the therapeutic action of the instant compositions.
- compositions and the pharmaceutical carrier or diluent will of course depend upon the intended route of administration, i.e. parenterally or by inhalation.
- the compositions will be in a form suitable for administration by inhalation.
- the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer.
- the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container.
- the compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device.
- the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in less, equal or greater amounts than the solid active ingredient.
- the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampul or an aqueous or nonaqueous liquid suspension.
- a compound of general formula (I) is administered to an animal or human subject in a composition comprising an amount sufficient to produce an inhibition of the symptoms of an allergic response.
- the dosage of the composition is such that from 0.5 mg. to 500 mg. of active ingredient are administered at each administration.
- equal doses will be administered 1 to 4 times daily with the daily dosage regimen being selected from about 0.5 mg. to about 2000 mg.
- the resultant mixture was stirred at ambient temperature for about 16 hours.
- the reaction mixture was filtered and the filtrate concentrated at reduced pressure to afford a crude product.
- the crude product was partitioned between ethyl acetate and dilute hydrochloric acid.
- the ethyl acetate fraction was washed with water, dried over anhydrous sodium sulfate and filtered.
- To the filtrate was added slowly n-hexane until the solution became turbid. Upon standing, white crystals, with a melting point of about 124°C., with decomposition were obtained.
- alkali metal salts of the compounds of the present invention may be prepared.
- an active ingredient such as N,N'- bis[7-f4-chlorobenzoylmethylsulfonyl)-1,2,3,4-tetrahydroisoquinolyl]disulfonylimide, is dissolved in sterile water at a concentration of 0.5% and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired aerosolized weight of drug.
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Abstract
Description
- This invention relates to novel imidodisulfamides which are useful as end-organ antagonists or slow reacting substance of anaphylaxis, pharmaceutical compositions and methods of inibiting the symptoms of an allergic response. The substance, SRS-A, has been suggested to be an important mediator of anaphylaxis in human asthma. By antagonizing the effects of this or other pharmacologically active mediators at the end-organ, bronchial smooth muscle, the compounds of this invention are valuable in the treatment of allergic diseases such as asthma.
- The imidodisulfamide compounds of this invention are represented by the following general structural formula (I):
- Particular compounds of the instant invention are compounds of the general formula (I) wherein:
- (a) R2 is hydrogen and R1 is hydrogen; 3- or 4-bromo; 2-, 3- or 4-chloro; 3-nitro; 3- or 4-trifluoromethyl; or 4-methoxy;
- (b) R2 is 3-chloro and R, is 4-chloro or 4-methyl;
- (c) R2 is 4-chloro and Ri is 3-trifluoromethyl; and
- (d) R2 is 3-methyl and R1 is 4-methyl.
- Specific compounds of the instant invention are the compounds of the general formula (I) wherein R2 is hydrogen and R1 is 4-bromo or 4-chloro.
-
- Examples of such non-nucleophilic organic bases include tertiary alkylamines, such as triethylamine, tertiary alkylaryl amines, such as N,N-dimethylaniline and aromatic amines, such as pyridine.
- The reaction is carrried out in an inert polar organic solvent. The selection of a particular solvent is not critical provided that the solvent is substantially inert to the reagents and product. Illustrative of such a solvent is acetonitrile.
- The reaction is usually carried out at moderate to low temperatures. For example, the reagents are usually mixed at temperatures of 0°C. or less and the reaction is allowed to warm gradually to ambient temperature.
- The reaction time is dependent on inter alia the particular starting materials, solvent and reaction temperature. Generally, the reaction will be allowed to proceed for at least 12 hours.
- The reaction product can be isolated by standard methods, for example, addition of dilute mineral acid e.g. hydrochloric acid, to the reaction mixture affords the compounds of general formula (1) as the "free acid".
- Alkali metal salts of the compounds of the general formula (I), for example, the sodium or potassium salts, are obtainable by treatment of the compounds with the appropriate metal alkoxide, for example methoxide, in an alkanol solvent such as methanol; by treatment of the compounds with an alkali metal hydride, such as sodium hydride or potassium hydride, in a polar non-protic solvent, such as tetrahydrofuran, or dimethoxyethane; or by treatment of the compounds with a cationic exchange resin, such as sulfonic acid resin in the sodium form.
- The starting appropriately substituted tetrahydroisoquinolines of the general formula (A) are conveniently prepared by standard reactions well known in the chemical arts as shown below:
- The SRS-A antagonist activity of the compounds of this invention is measured by the ability of the active medicament to inhibit SRS-A induced contraction of guinea pig ileum. In this test system, sections of ileum are resected from guinea pigs and placed in 5 ml. tissue baths containing a modified Tyrode's solution. One end of the tissue is fixed to a glass tissue holder, the other is connected to a force-displacement transducer and the tissue is placed under a tension of 500 mg. Isometric tissue contractions are recorded on a six channel polygraph. Baths are constantly aerated with 95% O2―5% CO2, After a 20 minute stabilization period a concentration of the appropriate agonist which provides a contraction height of 60-80% of the maximum obtainable to that agonist (as determined from full sequential concentration - response curves in separate experiments) is added to the tissue bath and the response recorded. The procedure is repeated until reproducible responses are obtained. For most agonists, two applications in rapid succession, followed 15 minutes later by a third, is sufficient to establish reproducibility. Experimental tissues are incubated with the selected concentration of the test compounds for 1 minutes. Experimental and control tissues are subjected to 5 bath changes during the incubation interval. Changes in bath fluid during the incubation period are helpful in insuring the reproducibility of tissue responses to the agonist. The same concentration of the agonist is reapplied in the presence of the test compound and the response registered and compared with controls. Percent inhibition produced by the test compound is calculated by subtracting the mean percentage change in control tissue from the mean percentage change in tissues exposed to the test compound. Additional compounds are then evaluated as long as the tissue remains reproducibly responsive to the agonist. Six tissues obtained from 6 animals are used simultaneously - 3 controls and 3 experimental.
- The compounds of this invention tested at concentrations of from 5 x 10-5M to 1 x 10-6M produce marked antagonism or partially purified slow reacting substance of anaphylaxis obtained from guinea pig lung. The agonist is employed at a concentration of 40,ug/ml.
- At a compound concentration of 5 x 10-6M, N,N'-bis[7-(4-chlorobenzoylmethylsulfonyl)-1,2,3,4-tetrahydroisoquinoyl]disulfonylimide exhibited 60 percent antogonism.
- The specificity of the antagonist activity of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, serotonin, histamine and the prostaglandins F2,, and E2.
- Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the general formula (1) or an alkali metal salt thereof sufficient to produce the inhibition of the symptoms of asthma and other allergic diseases.
- When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as, stabilizers, antioxidants, preservatives, lubricants, suspending agents and viscosity modifiers, provided that the additional ingredients do not have detrimental effect on the therapeutic action of the instant compositions.
- The nature of the composition and the pharmaceutical carrier or diluent will of course depend upon the intended route of administration, i.e. parenterally or by inhalation.
- In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer. Alternatively the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container. The compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device. In the above compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in less, equal or greater amounts than the solid active ingredient.
- For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampul or an aqueous or nonaqueous liquid suspension.
- Usually a compound of general formula (I) is administered to an animal or human subject in a composition comprising an amount sufficient to produce an inhibition of the symptoms of an allergic response. When employed in this manner, the dosage of the composition is such that from 0.5 mg. to 500 mg. of active ingredient are administered at each administration. For convenience equal doses will be administered 1 to 4 times daily with the daily dosage regimen being selected from about 0.5 mg. to about 2000 mg.
- The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
- The following examples illustrate the preparation of compounds of general formula (I) and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto.
- A mixture of 166 g. (1.42 mole) of chlorosulfonic acid and 202 g. (1.42 mole) of chlorosulfonylisocyanate was heated under reflux (110°C). in an oil bath until the evolution of carbon dioxide ceased. The crude product was distilled in vacuo to yield bis(chlorosulfonyl)imide, b.p., (1.5 mm.) 100°C., which is used as described hereinafter.
- To 0.42 g (1.95 mmol.) bis(chlorosulfonyl)imide in 20 ml. dry acetonitrile at -40°C. was added dropwise 0.59 g. (5.85 mmol.) dry triethylamine. The reaction mixture was warmed to 0°C. and 1.50 g. (3.89 mmole.) 7-(4-chlorobenzoylmethylsulfonyl)-1,2,3,4-tetrahydroisoquinoline in 0.39 g. (3.89 mmole) triethylamine, 10 ml. acetonitrile and 10 ml. methylene chloride was added slowly. The resultant mixture was stirred at ambient temperature for about 16 hours. The reaction mixture was filtered and the filtrate concentrated at reduced pressure to afford a crude product. The crude product was partitioned between ethyl acetate and dilute hydrochloric acid. The ethyl acetate fraction was washed with water, dried over anhydrous sodium sulfate and filtered. To the filtrate was added slowly n-hexane until the solution became turbid. Upon standing, white crystals, with a melting point of about 124°C., with decomposition were obtained.
- Similarly, following the above procedure, the appropriately substituted tetrahydroisoquinoline may be reacted with bis(chlorosulfonyl)imide to afford the compounds of general formula (I) as listed in the following table:
-
- A solution of N,N'-bis[7-(4-chlorobenzoylmethylsulfonyl)-1,2,3,4-tetrahydroisoquinolyl]-di- sulfonylimide in methanol is passed through an ion exchange column (IR 120-sulfonic acid type in the sodium form) and the column eluted with methanol. The eluant is concentrated to near dryness and the resultant material is triturated with diethyl ether which after filtration under nitrogen affords the desired salt.
- Similarly, alkali metal salts of the compounds of the present invention may be prepared.
- As a specific embodiment of a composition of this invention an active ingredient, such as N,N'- bis[7-f4-chlorobenzoylmethylsulfonyl)-1,2,3,4-tetrahydroisoquinolyl]disulfonylimide, is dissolved in sterile water at a concentration of 0.5% and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired aerosolized weight of drug.
Claims (9)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT81305796T ATE8137T1 (en) | 1981-01-05 | 1981-12-08 | ANTIALLERGIC IMIDODISULFAMIDES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICALS CONTAINING THEM. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/222,478 US4385047A (en) | 1981-01-05 | 1981-01-05 | Antiallergic imidodisulfamides |
US222478 | 2002-08-16 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0055899A2 EP0055899A2 (en) | 1982-07-14 |
EP0055899A3 EP0055899A3 (en) | 1982-09-08 |
EP0055899B1 true EP0055899B1 (en) | 1984-06-27 |
Family
ID=22832388
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP81305796A Expired EP0055899B1 (en) | 1981-01-05 | 1981-12-08 | Antiallergic imidodisulfamides, process for their production and pharmaceutical compositions containing them |
Country Status (8)
Country | Link |
---|---|
US (1) | US4385047A (en) |
EP (1) | EP0055899B1 (en) |
JP (1) | JPS57134468A (en) |
AT (1) | ATE8137T1 (en) |
DE (1) | DE3164472D1 (en) |
DK (1) | DK382A (en) |
GR (1) | GR76984B (en) |
IE (1) | IE51884B1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1582884A (en) * | 1977-05-19 | 1981-01-14 | Beecham Group Ltd | Clavulanic acid derivatives their preparation and use |
DK330880A (en) * | 1979-08-03 | 1981-02-04 | Beecham Group Ltd | PROCEDURE FOR THE PREPARATION OF CLAVULANIC ACID DERIVATIVES |
EP0053893B1 (en) * | 1980-12-09 | 1985-03-20 | Beecham Group Plc | Derivatives of clavulanic acid, their preparation and their use |
NZ199200A (en) * | 1980-12-23 | 1984-07-31 | Beecham Group Ltd | Clavulanic acid derivatives and pharmaceutical compositions |
KR20180083896A (en) | 2015-11-13 | 2018-07-23 | 론자 리미티드 | Process for producing bis (fluorosulfonyl) -imide and salt thereof |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE24763E (en) | 1960-01-12 | Ch ch j | ||
US3062813A (en) * | 1960-05-13 | 1962-11-06 | Pennsalt Chemicals Corp | Novel synthesis of sulfonamides |
GB1384530A (en) * | 1971-07-29 | 1975-02-19 | Fisons Ltd | Chromone derivatives |
AT352135B (en) * | 1975-07-30 | 1979-09-10 | Thomae Gmbh Dr K | Process for the preparation of new homophthalimides and their salts |
JPS5484035A (en) * | 1977-12-16 | 1979-07-04 | Tanabe Seiyaku Co Ltd | Anti-allergic agent |
US4252818A (en) * | 1979-08-02 | 1981-02-24 | Merck & Co., Inc. | Novel benzopyran derivatives |
US4228170A (en) * | 1979-08-30 | 1980-10-14 | Smithkline Corporation | 7- and/or 8-Sulfur substituted 1,2,3,4-tetrahydroisoquinoline compounds |
US4315935A (en) * | 1980-04-14 | 1982-02-16 | Smithkline Corporation | N,N'-Bis[substituted-1,2,3,4-tetrahydroisoquinolinolyl]disulfonylimides and antiallergic compositions and method of use |
US4317826A (en) * | 1980-05-27 | 1982-03-02 | Smithkline Corporation | N,N'-Bis[substituted-1,2,3,4 tetrahydroisoquinolyl]disulfonylimides and antiallergic compositions and method of use |
US4296129A (en) * | 1980-10-29 | 1981-10-20 | Pfizer, Inc. | (Carboxyacylamino)phenylalkenamides and esters thereof as SRS-A antagonists |
-
1981
- 1981-01-05 US US06/222,478 patent/US4385047A/en not_active Expired - Fee Related
- 1981-12-08 EP EP81305796A patent/EP0055899B1/en not_active Expired
- 1981-12-08 AT AT81305796T patent/ATE8137T1/en not_active IP Right Cessation
- 1981-12-08 DE DE8181305796T patent/DE3164472D1/en not_active Expired
- 1981-12-28 JP JP56216056A patent/JPS57134468A/en active Pending
-
1982
- 1982-01-04 IE IE2/82A patent/IE51884B1/en unknown
- 1982-01-04 DK DK382A patent/DK382A/en not_active Application Discontinuation
- 1982-01-04 GR GR66939A patent/GR76984B/el unknown
Also Published As
Publication number | Publication date |
---|---|
IE820002L (en) | 1982-07-05 |
GR76984B (en) | 1984-09-04 |
IE51884B1 (en) | 1987-04-15 |
JPS57134468A (en) | 1982-08-19 |
EP0055899A3 (en) | 1982-09-08 |
DK382A (en) | 1982-07-06 |
DE3164472D1 (en) | 1984-08-02 |
EP0055899A2 (en) | 1982-07-14 |
US4385047A (en) | 1983-05-24 |
ATE8137T1 (en) | 1984-07-15 |
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